tbuckley/cabot-search huggingface dataset:
Phase I study of NEROFE and doxorubicin in <i>KRAS</i>-mutated ST2-positive solid tumors.
Authors: Benjamin Adam Weinberg, Hongkun Wang, Joshua E. Reuss, Sosipatros Alexandros Boikos, Elaine M. Walsh, Chul Kim, Aiwu Ruth He, Marcus Smith Noel, Ann Wild Gramza, Geoffrey Thomas Gibney, Stephen V. Liu, Laura Ann Macke, Jennifer E. Montcalm, Kerrie Bouker, Joel Ohana, Uziel Sandler, Yoram Devary
Journal: Journal of Clinical Oncology (2023)

TPS2667 Background: KRAS-mutated tumors are notoriously difficult to treat clinically with targeted therapies. Recent advances targeting KRAS G12C with sotorasib and adagrasib are encouraging but limited to a small subset of patients. NEROFE is a 14 amino acid peptide which inhibits suppression of tumorigenicity 2 (ST2; member of the interleukin 1 [IL-1] receptor family and IL-33 receptor), a novel immune checkpoint present on tumor cells and tumor-associated macrophages. ST2 blockade with NEROFE has been shown to transform an immunosuppressive tumor microenvironment into an immune-stimulatory microenvironment. NEROFE also has been shown to induce microRNA miR-217 which downregulates KRAS and MAPK1/2 gene expression in preclinical models. When combined with low-dose doxorubicin, NEROFE has a synergistic effect on inducing apoptosis in KRAS-mutated, ST2-positive cell lines and xenograft models. Methods: This is a phase I trial of NEROFE given at 48 mg/m 2 (dose level [DL] -1), 96 mg/m 2 (DL1), 192 mg/m 2 (DL2), or 288 mg/m 2 (DL3) IV weekly with doxorubicin 8 mg/m 2 IV weekly. A standard 3+3 dose escalation/de-escalation is used. The primary objective is to determine the recommended phase II dose. Patients are eligible if they have an advanced solid tumor with a KRAS mutation and ST2-positivity (via immunohistochemistry [IHC], centrally confirmed with pre-screening allowed). Patients must have measurable disease amenable to serial biopsy. Patients must have had progression or intolerance to all standard therapies or must decline available standard therapy. Pharmacokinetic profiles will be analyzed from serial blood draws pre- and 1, 2, 4, 6, and 24 hours post-infusion on cycle 1 day and cycle 2 day 1. Pre- and on-treatment tumor biopsies are mandatory. Correlative studies include IHC for ST2 expression, immune cell infiltration and blood-based analyses of KRAS mRNA, miR-217, and cytokines. Enrollment to DL1 began in Q1 2023 (NCT05661201). Clinical trial information: NCT05661201 .
A web-based prediction model for overall survival of elderly patients with epithelial ovarian cancer: A population-based study.
Authors: Lingliya Tang, Kun Song, Ran Chu, Zhongshao Chen, Yong Zhao, Shuaixin Wang
Journal: Journal of Clinical Oncology (2023)

e17570 Background: Epithelial ovarian cancer (EOC) has been extensively studied. However, no prediction model has been carried out on the prognosis of elderly patients. Our study aims to explore survival patterns in elderly EOC patients. Methods: Data were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. Patients over 65 with EOC between 2004 and 2014 were included for model training and validation, while 2015 for external validation. COX proportional-hazards regression model was used to identify risk factors and applied them to the prediction model. We then evaluated performance of our model through receiver operating characteristic (ROC) curve, calibration curve and decision curve analysis (DCA). Risk stratification system was used to reflect the survival. To facilitate daily use, we developed an online application. Results: A total of 6141 patients were included. COX regression models indicated 10 independent risk factors. Our model was proved to have good performance with AUC of ROC curve: 0.768(95CI:0.749-0.788), 0.748 (95CI:0.733-0.763), 0.766 (95CI:0.750-0.781) for 1-, 3-, 5-year OS in the training cohort and 0.776 (95CI:0.757-0.796), 0.760 (95CI:0.745-0.775), 0.784 (95CI:0.769-0.799) for CSS. In the validation cohort, 0.800 (95CI:0.773-0.827), 0.770 (95CI:0.748-0.793), 0.787 (95CI:0.765-0.810) for OS and 0.808 (95CI:0.780-0.836), 0.780 (95CI:0.758-0.803), 0.801 (95CI:0.779-0.824) for CSS. In the risk stratification system, the low-risk group had the highest survival rate. Almost all patients in the low- and intermediate-risk groups underwent surgery, about 1/3 patients in the high-risk group did not receive surgery. Their survival rates were not optimistic, and patients over 85 were more likely to be classified as high-risk. Conclusions: A predictive model was constructed to evaluate survival for elderly EOC patients and demonstrated good predictive value that we can apply to help physicians make clinical decisions and plan treatment. [Table: see text]
Analysis of tumor progression among patients with glioma after COVID-19 infection.
Authors: Tim Gregory, Stephanie Knight, Ashley Aaroe, Barbara Jane O'Brien, Chirag B Patel, Shiao-Pei S. Weathers, Nazanin Majd, Vinay K. Puduvalli, Carlos Kamiya-Matsuoka
Journal: Journal of Clinical Oncology (2023)

2041 Background: As of January 2023, there have been 6.7 million worldwide deaths attributed to SARS-CoV-2 COVID-19, which has impacted outcomes and medical care for all patients. Relatively little is known about the direct effects mediated by the virus on CNS tumor biology, despite the fact that viral neurotropism is well described, various coronavirus receptors have been observed in glioblastoma (GBM) tissues, and differential monocytic infiltration has been proposed to dysregulate the immune microenvironment. We detected a trend of rapid progression following COVID-19 infection among several patients with primary brain tumor patients and sought to systematically evaluate the pace of progression among infected patients in our institution. Methods: A single-institutional database of COVID-19 patients and an electronic medical record (EMR) search tool were used to identify a total cohort of 67 patients with glioma for retrospective analysis. This included 38 GBMs, 18 IDH-mutant gliomas, 5 ependymomas, 2 pilocytic astrocytomas, 1 diffuse midline glioma, 1 diffuse hemispheric glioma, and 1 ganglioglioma patients, each of whom had a documented COVID-19 infection between June 2020-December 2022. Hyperprogression was defined as tumor increase ≥40% compared to previous scan using RECIST size criteria. Results: Thirty-nine (58%) patients experienced tumor progression following COVID-19 infection at a median of 34 days (range=1-734 days) after testing positive for COVID-19. Twenty-two (56%) had received COVID-19 vaccine before their infection and 5 (13%) had asymptomatic infections. Twenty-two patients had measurably increased tumor area by a median of 63% (range=10-2,900%), 18 of which constituted hyperprogression;16 patients developed multifocal disease, 8 developed new nodular enhancement, 3 developed leptomeningeal disease (LMD), and 2 experienced increased infiltrative disease alone. Ten patients’ presentation with new glioma was preceded by COVID-19 infection by a median of 31 days. GBM patients represented the majority of progression events, among whom 59% progressed within 60 days of documented infection (median 25 days). This subgroup of GBM with rapid progression within 60 days had a mOS from infection of 5.2 months; 89% had TERT promotor mutations and 42% had MGMT promoter methylation. Conclusions: Glioma patients appear to have disease progression at an accelerated pace in the first two months after COVID-19 infection. This suggests that glioma patients should continue observing strict precautions to prevent infection and should be clinically monitored vigilantly after infection, with consideration for short interval imaging during treatment. These preliminary data warrant further investigation exploring changes of immune cell infiltration in the tumor microenvironment and the possible correlation between tumor progression and COVID-19.
A comprehensive pan-cancer analysis of PD-L1 expression using clone E1L3N in Chinese patients with cancer.
Authors: Huangbin Lu, Zhan Huang, Huijuan Ge, Hongyu Wang, Li Ruan, Frank Zheng
Journal: Journal of Clinical Oncology (2023)

2656 Background: Immune checkpoint inhibitors (ICIs) benefit patients with multiple cancer types, and the expression of programmed death ligand 1 (PD-L1) protein assessed by immunohistochemistry (IHC) has been correlated with response and survival benefit from anti-PD-1/PD-L1 ICI therapies in several cancer types. IHC assay with E1L3N clone is currently approved by the NMPA for PD-L1 detection in non-small cell lung cancer (NSCLC), but its performance in other cancer types needs to be further validated. Thus, we performed this study to examine the prevalence of PD-L1 expression in a wide variety of tumor types in Chinese pan-cancer patients using the E1L3N antibody clone. Methods: From 2019 to 2022, a total of 13,647 patient across multiple tumor types were analyzed. Tumor tissue samples were subjected to IHC. PD-L1 expression was tested using the E1L3N PD-L1 IHC assay (Amoy Diagnostics, Xiamen, China), and scored with the tumor proportion score (TPS) and combined positive score (CPS). PD-L1 expression status was identified as positive and negative according to TPS or CPS. For NSCLC: negative (TPS &lt; 1%), low expression (TPS 1-49%), and high expression (TPS ≥ 50%). For gastric/gastroesophageal junction carcinoma (GC/GJC): negative (CPS &lt; 1), low expression (CPS 1-5), and high expression (CPS ≥ 5). For other cancer: negative (CPS &lt; 1), low expression (CPS 1-10), and high expression (CPS ≥ 10). Results: In total, 14 cancer types were enrolled in the present study, including 68.2% NSCLC, 6.9% colorectal carcinoma (CRC), and 3.8% GC/GJC, and the remaining 21.1% include esophageal cancer (EC), breast cancer, cervical cancer (CC), biliary tract cancer (BTC), pancreatic cancer (PC), ovarian cancer, renal cancer, small cell lung cancer, urothelial carcinoma (UC), bladder cancer, head and neck squamous cell carcinoma (HNSCC), etc. PD-L1 positivity by TPS was observed in 52.5% NSCLC patients, similar to the frequency of PD-L1 expression in Chinese NSCLC patients detected using 22C3 clone. 76.0% and 36.7% of GC/GJC patients with PD-L1-positive tumors at a CPS cutoff of ≥ 1 and ≥ 5, respectively. PD-L1 positive expression frequency was higher than that in western GC/GJC patients detected using 22C3 and 28-8 clone (as reported from previous research: PD-L1 positivity with CPS ≥ 1 was 45.5% using the 22C3 assay and 49.1% using the 28-8 assay). 73.6% and 17.5% of CRC patients with PD-L1-positive tumors at a CPS cutoff of ≥ 1 and ≥ 10, respectively. In addition, 8 tumors (EC, CC, breast cancer, PC, BTC, UC, HNSCC, and bladder cancer) had the prevalence of PD-L1 CPS ≥ 1 greater than 50%. Conclusions: E1L3N can be used as a reliable alternative antibody clone to evaluate PD-L1 expression status not only in NSCLC patients but also in other cancer types.
Time-dependent efficacy of immune checkpoint inhibitors in the treatment of metastatic cancers: A meta-analysis.
Authors: Thierry Landre, Abdoulaye Karaboue, Zachary S Buchwald, Pasquale Innominato, David C Qian, Jean-baptiste Assie, Christos Chouaid, Francis Levi, Boris Duchemann
Journal: Journal of Clinical Oncology (2023)

2562 Background: Immune checkpoint inhibitors (ICIs) have been established as the standard of care for numerous advanced malignancies. Emerging evidence suggests that the time-of-day of administering these immunotherapies may impact patient outcomes. We sought to determine the consistency in the impact of ICI time-of-day infusion on survival of patients with metastatic cancer. Methods: We performed a meta-analysis of published studies that have reported on ICI time-of-day infusion and efficacy in patients with advanced solid tumors. Overall survival (OS) and progression free survival (PFS) were compared between patients who had received ICIs before and after the daily time cut-off of each study. Hazard ratios (HRs) with their 95% confidence interval (CI) were collected from the studies and pooled. Results: This meta-analysis identified 7 studies of 1019 patients (PS 0, 43%; PS 1, 39%; males, 65%; females, 35%) who had stage IV non-small cell lung cancer (NSCLC), urothelial cancer, renal cell carcinoma, or melanoma, and were treated with mostly anti-PD-1 (nivolumab or pembrolizumab), anti-PD-L1 (atezolizumab), and anti-CTLA-4 (ipilimumab) agents. The time cut-offs selected to stratify patterns of ICI infusion were 16:00 or 16:30 in 5 studies (based on differences in adaptive immune response reported in previous vaccination studies) and 13:00 (based on median time of ICI infusions) in 2 studies. The pooled analysis of OS results showed a statistically significant benefit in favor of patients receiving infusions in the morning or in the early part of the day with a HR: 0.49, [95% CI: 0.36-0.69] (p &lt; 0.0001). A similar benefit was observed for PFS with a HR: 0.56, [0.44-0.72] (p &lt; 0.00001). Conclusions: Patients with advanced cancers may benefit from earlier time-of-day ICI infusions. Our findings are consistent with established circadian mechanisms that control immune cell functions and trafficking over a 24-h period. Prospective randomized trials are warranted to establish ICI timing recommendations for optimizing treatment efficacy in patients with different cancer types and at minimal cost.
A deep learning system to predict origins for cancers of unknown primary using cytological images from hydrothorax and ascites.
Authors: Fei Tian, Lin Sun, Na Wei, Wei Liu, Xiangchun Li, Gong Chen
Journal: Journal of Clinical Oncology (2023)

e13628 Background: Cancer of unknown primary (CUP) origin is still a mystery in the field of tumor diagnosis, which is difficult to be diagnosed by conventional imaging methods. The aim of this study is to develop a deep learning based method to assist pathologists in determining the origin of malignant hydrothorax and ascites using cytological images. Methods: By curating cytology images of hydrothorax and ascites from 42682 cases at three hospitals, we developed a deep-learning-based method -Tumor Origin diffeRentiation for Cytological Histology (TORCH)- for diagnosis of malignancy and prediction of tumor origin. We examined its performance on three individual test sets (n=12799). We compared TORCH with a panel of four pathologists on 496 cases that were randomly selected from test sets. Area under the receiver operating characteristic curve (AUROC) was used as the primary classification metric. Metrics including accuracy, sensitivity, specificity, precision and negative predictive value were used to measure the efficacy of TORCH versus pathologists. A score system was used to evaluate and compare the performance between our AI model and pathologist experts. Attention heatmap was used to interpret model prediction results. Results: TORCH model reached an overall micro-average one versus rest auroc of 0.957(95% CI: 0.955-0.959). On the three test sets, TORCH achieved an AUROC of 0.964 (95% CI 0.957-0.972), 0.947 (0.940-0.953), and 0.988 (0.985-0.993) in the diagnosis of cancer and 0.947 (0.942-0.952), 0.957 (0.953-0.960) and 0.972 (0.968-0.976) in localization of tumor origin, respectively. For primary tumor origin prediction, TORCH achieved an overall top-1 accuracy of 79.2% and top-3 accuracy of 98.5%. On three test sets, the top-1 accuracy was 75.7%, 79.4%, and 85.0% respectively. Compared with pathologists, TORCH demonstrated a better prediction efficacy (1.665 ± 0.677 vs. 1.265 ± 0.555; P &lt;0.001). The mean diagnostic score of junior pathologists assisted with TORCH was also remarkably higher than the previous one (1.326 ± 0.728 vs. 1.101 ± 0.824; P &lt;0.001). The comprehensive accuracy of attention heatmaps capturing main area of isolated tumor cells was 87.3% (95% CI: 81.9-92.8%). Conclusions: TORCH model was able to provide relatively accurate diagnosis of malignancy and prediction of tumor cell origin in hydrothorax and ascites. It can be used as an effective ancillary method to aid clinicians in allocating personalized therapy and improving patients’ prognosis.
Do corticosteroids affect immunotherapy efficacy in malignancy? A systematic review.
Authors: Yoni Byron, Sonya Yegorova-Lee, Martin Tio
Journal: Journal of Clinical Oncology (2023)

e14692 Background: Early studies indicate that corticosteroids may limit survival benefits from immunotherapy, although this finding is potentially confounded by the poor prognosis of patients who require corticosteroids due to cancer-related symptoms. We conducted this systematic review to evaluate the effect corticosteroids have on immunotherapy, when adjusted for potentially confounding effects of corticosteroids given for palliative indications. Methods: 3 databases (PubMed, Embase, and Medline) were searched on 1st of February 2023. Studies that measured response or survival in patients receiving immunotherapy, while receiving corticosteroids for non-cancer indications, compared to either no corticosteroids or corticosteroids for cancer-related indications were included. Studies exclusively evaluating the effect of corticosteroids administered for immune-related adverse events were excluded to avoid immortal time bias. Pooled odds and hazard ratios with 95% confidence intervals (CI) were calculated using a random effects model. Study heterogeneity was assessed using the I 2 statistic, and publication bias was evaluated by funnel plot and Egger's regression model. Results: 8,426 studies were identified, of which 8 studies met our inclusion criteria for meta-analysis. Administration of steroids has no statistically significant effect on survival and response to immunotherapy when administered for non-cancer related indications, with a pooled odds ratio for overall response rate 0.92 (95% CI 0.58-1.44); pooled hazard ratio (HR) for progression free survival 0.87 (95% CI 0.68-1.12); and pooled HR for overall survival 0.79 (95% CI 0.59-1.05). Conclusions: This systematic review indicates that administration of corticosteroids does not affect response to immunotherapy nor survival outcomes, when removing confounding palliative corticosteroid indications. Limiting or minimising corticosteroid treatment in this patient population due to concern of potential lowered efficacy of immunotherapy can therefore be reconsidered. These results are limited by the retrospective nature of the studies, small sample sizes, and the lack of information about corticosteroid dosing or length of treatment.
An exploratory trial of a novel R-ISV-RO technique in the treatment of advanced solid tumors.
Authors: Rutian Li, Limei Min, Xiaolu Wang, Anni Chen, Xiaofeng Chang, Lanqi Cen, Jun Chen, Wu Sun, Jing Yan, Xia Zhou, Jie Shen, Baorui Liu
Journal: Journal of Clinical Oncology (2023)

e14666 Background: The immunotherapy of bone and soft tissue sarcomas remains a challenge. Our pre-clinical trial confirmed that the combination of Toll-like receptor 7 (TLR7) agonist imiquimod (R837) and OX-40 agonist had prominent synergistic effects. Immunoradiotherapy, especially Stereotactic Body Radiotherapy (SBRT) could further activate specific immune response. We hypothesized that intratumoral injection of “RO” (R837+αOX40) combined with SBRT will realize tumor control and reduce adverse reactions. Meanwhile, the synergetic application of PD-1 mAb systematically will improve the effectiveness of immunotherapy. Methods: This is a single-arm, single-center, open-label, exploratory trial that explore intratumoral injection of an emulsion of “RO” in combination with SBRT as “in situ vaccination” for advanced solid tumor (Ethics number: 2021-133-02). The inclusion criteria included: 1) advanced solid tumors which progress after standard therapies, 2) presence of one or more injectable lesions. SBRT to injected lesions was at a dose of 5-8Gy per fraction at a total dose of 20-32Gy. Imiquimod (0.75mg/ml) and αOX40 (2.5mg/ml) were prepared as emulsion and intratumoral injected into the target lesion for 4 times. Patients were also systematically administrated with PD-1 mAb (serplulimab). The primary endpoint was objective response rate (ORR) of target lesions. The secondary endpoint mainly included disease control rate (DCR) of target lesions, progression free survival (PFS), overall survival (OS), and clinical benefit rate (CBR), etc. Results: From May 2021 to October 2022, 30 patients were eligible for this trial (60% were sarcomas). 46.7% and 33.3% had received radiotherapy or PD-1/PD-L1 mAb respectively before. The ORR, DCR and CBR of target lesions were 29.2%, 91.7% and 41.7%, while these of systemic efficacy were 21.7%, 82.6% and 17.4%, respectively. In sarcomas, the ORR, DCR and CBR of target lesions were 25.0%, 93.8% and 50.0%, while these of systemic efficacy were 20.0%, 93.3% and 26.7%, respectively. Systemic median PFS were 3.67 months. The median event-free survival (EFS) of target lesions and median OS were not reached. Among the evaluable target lesions, 6-month EFS was 85.7% in sarcomas (6/7) and 76.9% in all patients (10/13). The most common TRAEs were leukopenia (50%), hypoproteinemia (30%) and anemia (20%), demonstrating that treatment is tolerable. Grade≥3 treatment-related adverse events (TRAE) occurred in 3 patients, including myocarditis (6.7%) and thyroiditis (3.3%). Conclusions: In situ vaccination with “RO” emulsion, along with SBRT was tolerable and induced anti-tumor immunity, which would also trigger systemic response when synergized with PD-1 mAb. This in situ vaccination has been proved to be a promising option for advanced solid tumors especially for sarcomas. Clinical trial information: ChiCTR2100053870 .